A novel synthesis of spiro(imidazolidine-2,3′-benzo[b]thiophene) by one-pot reaction of arynes, aryl isothiocyanates and N-heterocyclic carbenes

Article abstract of DOI:10.1055/s-2007-980380

A novel synthesis of spiro(imidazolidine-2,3′-benzo[b]thiophene) by one-pot reaction of aryl isothiocyanates, N-heterocyclic carbenes and arynes using (phenyl)[2-(trimethyl-silyl)phenyl]iodonium triflate as precursor is reported. Georg Thieme Verlag Stutt

Full text of DOI:10.1055/s-2007-980380

LETTER
1533
A Novel Synthesis of Spiro(imidazolidine-2,3¢-benzo[b]thiophene) by One-Pot
Reaction of Arynes, Aryl Isothiocyanates and N-Heterocyclic Carbenes
N
a
ovel Syn
i
thesis
of
Spiro(im
n
idazolidine-2,3
¢
-be
X
nzo[
b
]thiophene) ue,a Yewei Yang,a Xian Huang*a,b
b
200032, P. R. of China
Fax +86(571)88807077; E-mail: huangx@mail.hz.zj.cn
Received 6 January 2007
containing a central carbon have been reported owing to
their poor stability.7 Especially, no reaction of carbon-
centered 1,3-dipoles with arynes was reported.8 Recently
2-arylthiocarbamoylimidazolinium inner salts have been
reported to be a unique type of stable ambident C–C–S
and C–C–N 1,3-dipolar system, which are able to undergo
highly efficient and regioselective 1,3-dipolar cyclo-
addition reactions.7c Herein we wish to report our results
on the 1,3-dipolar cycloaddition reactions of arynes gen-
erated from (phenyl)[2-(trimethylsilyl)phenyl]iodonium
triflate (1b),9 aryl isothiocyanate and N-heterocyclic
carbenes to synthesize spiro(imidazolidine-2,3¢-ben-
zo[b]thiophene) in one pot.
Abstract: A novel synthesis of spiro(imidazolidine-2,3¢-
benzo[b]thiophene) by one-pot reaction of aryl isothiocyanates, N-
heterocyclic carbenes and arynes using (phenyl)[2-(trimethyl-
silyl)phenyl]iodonium triflate as precursor is reported.
Key words: one-pot reaction, arynes, N-heterocyclic carbenes, aryl
isothiocyanates, spiro heterocyclic compounds
As one of the most important active intermediates, arynes
have attracted considerable attention for their synthetic
applications.1 The common way for the generation of
arynes is dehydrohalogenation of halogenated aromatic
compounds with strong bases, which is unfavorable for
the substrates bearing base-sensitive functional groups.
This disadvantage can be overcome by the Kobayashi
method that is employed for the generation of arynes
which involves elimination of trimethylsilyltriflate from
2-(trimethylsilyl)phenyl triflate (1a) under mild condi-
tions.2 Recently, the chemistry of 2-(trimethylsilyl)phenyl
triflate has been extended to insertion of s-bonds,3 multi-
component reactions4 and transition-metal-catalyzed re-
actions.5 Therefore, this aryne precursor has been widely
used in the construction of complex organic compounds
and polysubstituted arenes.
Initially, we examined the cycloaddition reaction of 1,3-
bis(2,4,6-trimethylphenyl)imidazolinium chloride (2a)
with one equivalent of 2-tolyl isothiocyanate (3a) in the
presence of 1.2 equivalents of NaH (65% in mineral oil)
at room temperature for 12 hours, which provided the 1,3-
bis(2,4,6-trimethylphenyl)-2-N-phenylthiocarbamoyl im-
idazolinium inner salt (4aa) in 97% yield (Scheme 1).10
The cycloaddition reaction of arynes with 4aa was then
studied (Scheme 2). When we treated one equivalent of
inner salt 4aa with one equivalent of 1a in the presence of
one equivalent of KF and one equivalent of 18-crown-6 in
THF (10 mL) at room temperature for 14 hours, a single
spiro product was obtained in 35% yield. The product
might be 5aa or 6aa according to the regioselectivity of
the reaction. In order to determine the pathway of the 1,3-
dipolar reaction, we tried to obtain the single crystal of the
spiro product. But we could not get the crystal because the
melting point of the spiro product is too low.
The addition of 1,3-dipolar compounds to alkenes and
alkynes has been developed extensively for the synthesis
of five-membered-ring heterocycles.6 Most of the 1,3-di-
polar systems reported to date contain a central hetero-
atom (N or O), because its lone-pair electrons can
participate in the stabilization of the dipolar resonance
structures. Only few examples of 1,3-dipolar compounds
Ar
Ar
N
Ar
N
S
S
C
N
NaH
THF
NCS
Me
3a
Cl
N
+
N
N
N
N
Me
Me
Ar
Ar
Ar
2a
4aa
Ar = 2,4,6-trimethylphenyl (mesityl)
Scheme 1
SYNLETT 2007, No. 10, pp 1533–1536
1
8
.0
6
.2
0
0
7
Advanced online publication: 07.06.2007
DOI: 10.1055/s-2007-980380; Art ID: W00207ST
© Georg Thieme Verlag Stuttgart · New York

1534
J. Xue et al.
LETTER
Mes
Mes
Mes
Mes
N
N
N
N
X
Y
S
Me
4aa
or
N
N
S
Me
5aa
6aa
Figure 1 X-ray crystal structure of 7aa
1a: X = TMS, Y = OTf, 14 h, 35%
1b: X = TMS, Y = I+PhOTf–, 15 min, 44%
1c: X = CO2–, Y = N2+, 4 h, 31%
In an attempt to improve the yield, subsequent work fo-
cused on the choice of the precursor of arynes. Another
two precursors 1b and 1c were selected, which are widely
used in arynes chemistry. When 1b was used as the pre-
cursor of aryne under the similar conditions, the spiro
product was obtained in 44% yield and the reaction was
complete within 15 minutes. However, when benzenedia-
zonium 2-carboxylate (1c)13 was chosen as the precursor
of aryne for this reaction, the reaction was complete in
four hours and the spiro product was isolated in 31%
yield. The experimental results showed that the precursor
1b has higher efficiency, which was consistent with the
previous report.9b Thus, phenyl iodonium triflate 1b was
chosen as the optimal precursor of aryne in the reaction.
Scheme 2
Fortunately the product could undergo a facile hydrolysis.
When the spiro product was treated with silica gel in
EtOH–H2O (1:1) at room temperature for 1.5 days, the hy-
drolyzed product was isolated in 81% yield (Scheme 3).
Recrystallization of the hydrolyzed product from ethanol
provided needle-shaped crystal for X-ray diffraction
studies.
From the X-ray analysis we could confirm that the struc-
ture of the hydrolyzed product was 7aa (Figure 1).11 So
the spiro compound was 1,3-bis(2,4,6-trimethylphenyl)-
2¢-(2-tolyliminio)-2¢,3¢-dihydrospiro(imidazolidine-2,3¢-
benzo[b]thiophene) (5aa) and the 1,3-dipolar cycloaddi-
tion reaction proceeds in the C–C–S fashion. In order to
explain the reaction pathway we calculated the energies of
5aa and 6aa on the basis of their RHF/STO-3G optimized
structures.12 The results showed that 5aa (32.99 kcal/mol)
has much higher relative energies than 6aa (0.00 kcal/
mol). The cycloaddition of aryne with 4aa proceeds
through a kinetically favored route to afford thiophene
adducts rapidly and irreversibly because arynes have
higher reactivity.
We then tried to conduct the above two-step reaction in
one pot. It was found that one equivalent of 1,3-bis(2,4,6-
trimethylphenyl)imidazolinium chloride (2a) reacted
smoothly with one equivalent of 2-tolyl isothiocyanate
(3a) in the presence of 1.2 equivalents of NaH within 12
hours and the subsequent cycloaddition reaction with one
equivalent of 1b in the presence of one equivalent 18-
crown-6 and one equivalent KF could finish in 15 min-
utes, affording the product 5aa in 45% yield (Scheme 4).
With this encouraging result, the 1,3-dipolar cycloaddi-
tion reaction of arynes generated from 1b was examined
carefully. As shown in Table 1, when the reaction was
carried out in the absence of KF and 18-crown-6, the
product 5aa was not obtained and 4aa was recovered
(Table 1, entry 2). By using two equivalents of 1b, two
equivalents of KF and two equivalents of 18-crown-6, the
reaction proceeded smoothly at room temperature to give
5aa in 52% yield (Table 1, entry 3). On increasing the
amount of 1b to 2.2 equivalents the yield of 5aa could not
be improved dramatically (Table 1, entry 4). Using two
equivalents of 1b and three equivalents of KF and 18-
crown-6 in THF at room temperature gave the product in
60% yield (Table 1, entry 5). But increasing the amount of
KF and 18-crown-6 up to four equivalents failed to in-
crease the yield of 5aa (Table 1, entry 6). Therefore, the
Mes
O
Mes
N
N
or
N
N
7aa
N
S
S
N
5aa
Me
Me
silica gel
EtOH, H2O, 1.5 d
or
Mes
O
Mes
N
S
S
Me
N
Me
6aa
8aa
Scheme 3
TMS
Mes
IPhOTf–
Mes
Mes
N
N
N
1b
NaH
THF
Cl–
NCS
+
N
KF, 18-C-6, THF
S
N
Me
3a
Me
Mes
2a
5aa
Scheme 4
Synlett 2007, No. 10, 1533–1536 © Thieme Stuttgart · New York

LETTER
Novel Synthesis of Spiro(imidazolidine-2,3¢-benzo[b]thiophene)
1535
Table 1 1,3-Dipolar Cycloaddition Reaction of Arynesa
entry 1 with entry 2; compare entries 1 and 6 with entry 9,
Table 2). It should be noted that the electron-donating
groups in the substrate 3 facilitated the reaction (Table 2,
entry 4), but we got only trace product when there was an
electron-withdrawing group in the substrate 3 (Table 2,
entry 5).
Entry
5 (mmol)
KF (mmol) 18-crown-6 Yield (%)
(mmol)
1
2
3
4
5
6
0.5
0.5
1
0.5
0
0.5
0
45
0
In summary, a novel synthesis of spiro(imidazolidine-
2,3¢-benzo[b]thiophene) by one-pot reaction of arynes,
aryl isothiocyanates and N-heterocyclic carbenes has been
developed. It is the first example of a reaction of 1,3-dipo-
lar compounds containing a central carbon atom with
arynes. Further studies including the generation methods
of arynes, the reaction mechanism and synthetic applica-
tion of arynes are ongoing in our laboratory.
1
1
52
50
60
61
1.1
1
1.1
1.5
2
1.1
1.5
2
1
a At ambient temperature, 2a (0.5 mmol) and 3a (0.5 mmol) in the
presence of NaH (0.5 mmol, 65% in mineral oil) for 12 h, then the
mixture was reacted with 1b in the presence of KF and 18-crown-6 in
THF (10 mL).
Acknowledgment
This work was supported by the National Natural Science Founda-
tion of China (20332060, 20472072).
optimized reaction conditions were two equivalents of 1b,
one equivalent of imidazolium salts and aryl isothiocyan-
ate, 1.2 equivalents of NaH, three equivalents of KF and
three equivalents of 18-crown-6 in anhydrous THF at
room temperature.
References and Notes
(1) For reviews see: (a) Kessar, S. V. In Comprehensive
Organic Synthesis, Vol. 4; Trost, B. M.; Fleming, I., Eds.;
Pergamon: Oxford, 1991, 483. (b) Pellissier, H.; Santelli,
M. Tetrahedron 2003, 59, 701. (c) Hart, H. In Supplement
C2: The Chemistry of Triple-Bonded Functional Groups;
Patai, S., Ed.; Wiley: Chichester, U.K., 1994, Chap. 18,
1017–1134.
Under these optimal reaction conditions, a series of imida-
zolium salts 2 and aryl isothiocyanates 3 were chosen for
this reaction. Typical results are summarized in Table 2.14
The yields of the spiro products dropped due to the steric
hindrance of the methyl group in the substrates (compare
(2) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett.
1983, 1211.
(3) (a) Liu, Z.; Larock, R. C. Org. Lett. 2003, 5, 4673. (b) Liu,
Z.; Larock, R. C. Org. Lett. 2004, 6, 99. (c) Yoshida, H.;
Minabe, T.; Ohshita, J. Chem. Commun. 2005, 3454.
(d) Tambar, U. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005,
127, 5340. (e) Yoshida, H.; Watanabe, M.; Ohshita, J.
Tetrahedron Lett. 2005, 46, 6729. (f) Yoshida, H.;
Watanabe, M.; Ohshita, J. Chem. Commun. 2005, 3292.
(g) Yoshida, H.; Watanabe, M.; Ohshita, J. Chem. Lett.
2005, 34, 1538. (h) Yoshida, H.; Shirakawa, E.; Honda, Y.
Angew. Chem. Int. Ed. 2002, 41, 3247. (i) Liu, Z.; Larock,
R. C. J. Am. Chem. Soc. 2005, 127, 13112. (j) Yoshida, H.;
Minabe, T.; Ohshita, J. Chem. Commun. 2004, 1980.
(4) Yoshida, H.; Fukushima, H.; Ohshita, J.; Kunai, A. Angew.
Chem. Int. Ed. 2004, 43, 3935.
(5) (a) Yoshida, H.; Ikadai, J.; Shudo, M. J. Am. Chem. Soc.
2003, 125, 6638. (b) Yoshida, H.; Tanino, K.; Ohshita, J.
Angew. Chem. Int. Ed. 2004, 43, 5052. (c) Yoshida, H.;
Tanino, K.; Ohshita, J. Chem. Commun. 2005, 5678.
(d) Yoshida, H.; Honda, Y.; Shirakawa, E. Chem. Commun.
2001, 1880.
(6) Gothelf, K. V.; Jørgensen, K. A. Chem. Rev. 1998, 98, 863.
(7) (a) Winberg, H. E.; Coffman, D. D. J. Am. Chem. Soc. 1965,
87, 2776. (b) Regitz, M.; Hocker, J.; Schössler, W.; Weber,
B.; Liedhegener, A. Justus Liebigs Ann. Chem. 1971, 748,
1. (c) Liu, M. F.; Wang, B.; Cheng, Y. Chem. Commun.
2006, 1215.
(8) For the reaction of 1,3-dipolar compounds containing a
central heteroatom with arynes, see: (a) Taylor, E. C.;
Sobieray, D. M. Tetrahedron 1991, 47, 9599.
Table 2 1,3-Dipolar Cycloaddition Reaction of Arynesa
TMS
Ar
Ar
N
Ar
IPhOTf –
N
N
1b
NaH
THF
Cl–
+
Ar' NCS
N
Ar'
KF, 18-C-6, THF
N
S
Ar
2
3
5
Entry
Ar
Ar1
Products Yield (%)b
1
2
3
4
5
mesityl
2-MeC6H4
Ph
4-MeC6H4
2-MeOC6H4
2-FC6H4
5aa
5ab
5ac
5ad
5ae
60
62
68
75c
trace
6
7
8
xylyl
2-MeC6H4
Ph
4-MeC6H4
5ba
5bb
5bc
63
65
70
9
10
2-tolyl
Ph
4-MeC6H4
5cb
5cc
67
73
a Reaction conditions: At ambient temperature, 2 (0.5 mmol) and 3
(0.5 mmol) were stirred in the presence of NaH (0.6 mmol, 65% in
mineral oil) for 12 h, then the mixture was treated with 1b in the pres-
ence of KF and 18-crown-6 in THF (10 mL).
b Isolated yields based on aryl isothiocyanate.
(b) Matsumoto, T.; Sohma, T.; Hatazaki, S.; Suzuki, K.
Synlett 1993, 843. (c) Hussain, H.; Kianmehr, E.; Durst, T.
Tetrahedron Lett. 2001, 42, 2245. (d) Kitamura, T.;
c Crude product.
Synlett 2007, No. 10, 1533–1536 © Thieme Stuttgart · New York

1536
J. Xue et al.
LETTER
126.6, 126.5, 124.5, 117.3, 17.7. MS (EI): m/z (%) = 253
Fukatsu, N.; Fujiwara, Y. J. Org. Chem. 1998, 63, 8579.
(e) Kurita, J.; Kakusawa, N.; Yasuike, S.; Tsuchiya, T.
Heterocycles 1990, 31, 1937.
(9.80) [M+], 149 (100). Anal. Calcd for C15H11NOS: C,
71.12; H, 4.38; N, 5.53. Found: C, 71.04; H, 4.43; N, 5.55.
Crystal data for 7aa: C15H11NOS, M = 253.31, T = 293 K,
monoclinic, space group: P–1/c, a = 4.1713 (12), b = 18.949
(5), c = 15.561 (4) Å, a = 90 (4)°, b = 85.469 (4)°, g = 89.231
(4)°, V = 1223.5 (6) Å3, Z = 4, rcalcd = 1.375 g cm–3,
absorption coefficient: 0.250 mm–1, reflections collected/
unique: 6951/2651 [R(int) = 0.1071], final R indices [I
>2s(I)] R1 = 0.0484, R2 = 0.0989. For the crystallographic
data in CIF, see CCDC: 641755.
(9) (a) Kitamura, T.; Yamane, M. J. Chem. Soc., Chem.
Commun. 1995, 983. (b) Kitamura, T.; Todaka, M.; Fujiwar,
Y. Org. Synth. 2002, 78, 104. (c) Kitamura, T.; Yamane,
M.; Inoue, K. J. Am. Chem. Soc. 1999, 121, 11674.
(d) Kitamura, T.; Aoki, Y.; Isshiki, S.; Wasai, K.; Fujiwara,
Y. Tetrahedron Lett. 2006, 47, 1709.
(10) Procedure for the Preparation of Compound 4aa: At
ambient temperature, 1,3-bis(2,4,6-trimethylphenyl)imid-
azolinium chloride (2a; 1 mmol) was mixed with phenyl
isothiocyanate 3a (1 mmol) in anhyd THF (20 mL), and then
NaH (1.2 mmol, 65% in mineral oil) was added. After 12 h
H2O (5 mL) was added to the mixture. The mixture was then
diluted with CH2Cl2 (15 mL) and washed. The organic layer
was dried over MgSO4, and concentrated to give inner salt
4aa as yellow crystal. Compound 4aa was further purified
by recrystallization from CH2Cl2 and PE, through which the
pure inner salt 4aa was obtained. Data of 4aa: yellow solid;
mp 252–253 °C. IR (KBr): 1548, 1511, 1480, 1280 cm–1. 1H
NMR (400 MHz, CDCl3): d = 7.25 (s, 4 H), 6.82–6.92 (m, 2
H), 6.67–6.71 (t, J = 8 Hz, 1 H), 5.96–5.98 (d, J = 8 Hz, 1 H),
(12) Frisch, M. J. Gaussian 03, Revision B.01, Gaussian Inc.,
Pittsburgh Pa, 2003.
(13) (a) Friedman, L.; Logullo, F. M. J. Org. Chem. 1969, 34,
3089. (b) Logullo, F. M.; Seitz, A. H.; Friedman, L. Org.
Synth. 1968, 48, 12. (c) Okuma, K.; Yamamoto, T.;
Shirokawa, T.; Kitamura, T.; Fujiwara, Y. Tetrahedron Lett.
1996, 37, 8883.
(14) Procedure for the Preparation of Compound 5: At
ambient temperature, imidazolinium salt 2 (0.5 mmol) was
mixed with aryl isothiocyanate 3 (0.5 mmol) in anhyd THF
(10 mL), and then NaH (0.6 mmol, 65% in mineral oil) was
added. After 12 h when the reaction was complete
4.16 (s, 4 H), 2.56 (s, 12 H), 2.27 (s, 6 H), 1.33 (s, 3 H). 13
C
(monitored by TLC), phenyl[2-(trimethylsilyl)phenyl]io-
donium triflate (1b; 1 mmol) and 18-crown-6 (1.5 mmol) in
THF (10 mL) were added to the mixture and then KF (1.5
mmol) was added. After completion of the reaction, the
mixture was diluted with EtOAc (10 mL) and washed with
H2O and brine. The organic layer was dried over MgSO4.
Removal of the solvent in vacuum, and purification of the
residue by silica gel chromatography with n-hexane–EtOAc
(10:1) as eluent gave the product 5. Selected data of 5aa:
low melting point solid. IR (neat): 1706, 1623, 1483, 1448
cm–1. 1H NMR (400 MHz, CDCl3): d = 7.96–7.98 (d, J = 8
Hz, 1 H), 7.59–7.63 (t, J = 8 Hz, 1 H), 7.34–7.38 (m, 2 H),
7.25–7.27 (m, 2 H), 7.18–7.20 (m, 1 H), 6.96–6.98 (d, J = 8
Hz, 1 H), 6.82 (s, 4 H), 3.15 (s, 4 H), 2.28 (s, 12 H), 2.27 (s,
3 H), 2.23 (s, 6 H). 13C NMR (100 MHz, CDCl3): d = 185.1,
157.1, 149.2, 144.5, 143.3, 136.9, 131.5, 130.8, 130.2,
129.7, 129.5, 128.1, 127.7, 126.8, 126.6, 126.5, 125.0,
117.3, 49.1, 20.5, 18.4, 17.8. MS (EI): m/z (%) = 531 (3.24)
[M+], 148 (100). Anal. Calcd for C35H37N3S: C, 79.05; H,
7.01; N, 7.90. Found: C, 78.96; H, 7.09; N, 7.93.
NMR (100 MHz, CDCl3): d = 165.3, 150.5, 139.6, 136.8,
130.9, 129.7, 129.5, 128.4, 125.8, 122.1, 119.7, 49.1, 21.0,
18.6, 16.9. MS (EI): m/z (%) = 455 (72.41) [M+], 441 (100).
Anal. Calcd for C29H33N3S: C, 76.44; H, 7.30; N, 9.22.
Found: C, 76.38; H, 7.37; N, 9.19.
(11) Procedure for the Preparation of Compound 7aa: The
mixture of 5aa (0.5 mmol) and silica gel (100 mg) in EtOH–
H2O (10 mL, 1:1) was stirred at ambient temperature. When
the reaction was complete (monitored by TLC), the mixture
was diluted with EtOAc (15 mL) and filtered. The organic
layer was dried over MgSO4. Removal of the solvent in
vacuum, and purification of the residue by silica gel
chromatography with n-hexane–EtOAc (10:1) as eluent
gave the product 7aa. Data of 7aa: yellow solid; mp 134–
136 °C. IR (KBr): 1706, 1591, 1309 cm–1. 1H NMR (400
MHz, CDCl3): d = 7.96–7.98 (d, J = 8 Hz, 1 H), 7.60–7.64
(t, J = 8 Hz, 1 H), 7.33–7.39 (m, 2 H), 7.23–7.29 (m, 2 H),
7.17–7.20 (m, 1 H), 6.96–6.98 (d, J = 8 Hz, 1 H), 2.23 (s, 3
H). 13C NMR (100 MHz, CDCl3): d = 185.0, 157.1, 149.2,
144.5, 143.30, 136.90, 130.8, 130.2, 128.1, 127.7, 126.8,
Synlett 2007, No. 10, 1533–1536 © Thieme Stuttgart · New York

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